Among tertiary care patients, newborn infants receive frequent red cell transfusions for the treatment of iatrogenic and physiologic anemia, placing these patients at risk for developing serious transfusion-related complications. Neonatal anemia is associated with identifiable but non-specific clinical signs. Since there are no agreed upon measurable transfusion criteria for neonates, unnecessary transfusions may be performed. At greatest risk are infants weighing <1,250 g at birth. These infants, who have small blood volumes, generally need frequent blood testing, due to the seriousness of their problems. Very low birth weight infants typically receive multiple blood transfusions before discharge, placing them at even greater risk for serious transfusion-related problems. Thus, it is imperative to develop better transfusion criteria for neonates as well as to develop alternate treatment and prevention strategies. One alternate strategy for the prevention of neonatal anemia in high risk infants is treatment with recombinant human erythropoietin (rhEp); this treatment could potentially decrease neonatal red cell transfusion needs by half. The safety and efficacy of this approach, however, are unproven. We hypothesize that, during neonatal development, factors regulating Ep production are different from those observed in more mature individuals. Specifically we hypothesize that this difference is due at least in part to a switch which occurs in the site of Ep production during mammalian development: in mid-fetal life, the liver functions as the sole organ of Ep synthesis; by late fetal life, the kidney begins to assume an increasingly important role; and by early infancy when the process is completed, the kidney provides 90-95% of the Ep produced. This project will utilize a sheep model to study the neonate's cardiovascular and erythropoietic response to anemia as well as to assess the safety and efficacy of rhep treatment. In Aim 1, the relationship of plasma Ep to anemia will be compared in newborn and adult sheep with respect to: 1) a quantitative assessment of oxygen supply and demand; 2) erythrocyte progenitor cell number and cell cycle status; and 3) the amount of Ep mRNA and the rate of mRNA transcription in liver and kidney. In Aim 2, pharmacokinetic system analysis will be used to determine (125)I-rhEp kinetic parameters in anemic newborn and adult sheep. In Aim 3, the liver-to-kidney switch in the site of Ep production will be estimated by quantifying pharmacokinetic parameters during anemia before and after vascular occlusion of both renal arteries. Finally, in Aim 4, pharmacodynamics of rhEp will be compared following the administration of rhEp to neonatal and adult sheep. These same animals will be studied to determine if repeated high dose Ep therapy results in a subsequent reduction in the capacity for Ep production. Information related to neonatal anemia and erythropoiesis is important in understanding which neonates will benefit from treatment with blood transfusion, rhEp, or with a combination of the two.